Methods of ring opening polymerization and catalysts therefor

ABSTRACT

A salt catalyst comprises an ionic complex of i) a nitrogen base comprising one or more guanidine and/or amidine functional groups, and ii) an oxoacid comprising one or more active acid groups, the active acid groups independently comprising a carbonyl group (C═O), sulfoxide group (S═O), and/or a phosphonyl group (P═O) bonded to one or more active hydroxy groups; wherein a ratio of moles of the active hydroxy groups to moles of the guanidine and/or amidine functional groups is greater than 0 and less than 2.0. The salt catalysts are capable of catalyzing ring opening polymerization of cyclic carbonyl compounds.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a division of, and claims the benefit of, pendingnonprovisional U.S. application Ser. No. 12/859,336 entitled “METHODS OFRING OPENING POLYMERIZATION AND CATALYSTS THEREFOR,” filed on Aug. 19,2010, herein incorporated by reference in its entirety.

BACKGROUND

The present invention relates to methods of ring opening polymerizationand catalysts therefor, and more specifically, to salt catalysts forring opening polymerizations.

Ring-opening polymerization catalysts have allowed access to advancedmaterials in areas as diverse as adhesives and drug delivery. The firstcatalysts for ring opening polymerization were inorganic materials(e.g., aluminum, zinc, and tin compounds), which demonstrated excellentfidelity and control needed for construction of higher order polymerarchitectures. Unfortunately, the residual metal remaining in theresultant polymers proved problematic for microelectronic applications.Consequently, organic compounds were investigated to replace highlyactive metal-containing catalysts. In 2001, the first ring openingpolymerization of lactide catalyzed by an organocatalyst,4-dimethylaminopyridine (DMAP), was demonstrated, setting the stage forfuture discoveries of phosphines, carbenes, and amidine/guanidines forthe polymerization of cyclic esters.

Transition metals are thought to catalyze the polymerization of cyclicesters (lactide, valerolactone, caprolactone, and the like) through acoordination-insertion mechanism. In comparison, organocatalyzedpolymerizations were originally postulated to go through an activationmechanism in which DMAP or other electron donating organic catalyst,acting as a nucleophile (Nuc:) as shown in Scheme 1, form an activatedcomplex with the monomer carbonyl, thereby lowering the activationenergy for subsequent attack by the weaker nucleophilic hydroxyl group.

More recently this activation theory was amended in order to account forthe theoretical computations suggesting that the activatedmonomer-catalyst complex is in an exceedingly high energy state. A lowerenergy pathway was proposed in which the catalyst (Nuc: in Scheme 2)activates the propagating hydroxyl group through hydrogen bonding.

This insight fostered the design of bifunctional catalysts (Nuc:/E inScheme 3, wherein Nuc:/E comprises one or more components) capable ofsimultaneously activating the hydroxyl group in addition toelectrophilic activation of the monomer carbonyl.

The synchronized activation of both nucleophile (e.g., hydroxyl group ofthe initiator) and electrophile (e.g., carbonyl of the cyclic ester)allows a combination of weaker forces to achieve ring openingpolymerization. This was demonstrated using various thiourea compounds,which also selectively activated the cyclic ester carbonyl while showingminimal affinity toward analogous linear esters (FIG. 1; Lohmeijer, etal., Macromolecules, 2006, vol 39(5), pp 8574-8583). This selectivityhelped to mitigate unwanted transesterification reactions that wouldotherwise contribute to increased polydispersity (i.e., broadening ofthe polymer molecular weight range). Moreover, selective carbonylactivation allowed weaker bases, for example (−)-sparteine andN,N-dimethylcyclohexylamine, to be used for hydroxyl activation whilestill retaining adequate polymerization kinetics. (−)-Sparteine andN,N-dimethylcyclohexylamine are otherwise not active catalysts for thering opening polymerization of lactide. The polymerization rate can beeffectively increased by the use of a more potent hydroxyl activator(such as an amidine or guanidine base), but these stronger bases alsopredispose the polymerization to transesterification side reactions, andthus higher polydispersities.

The structural diversity of cyclic carbonyl monomers for ring openingpolymerizations continues to expand. Accompanying this trend is agrowing need for organocatalysts having improved selectivity towardpolymer chain growth.

SUMMARY

Accordingly, a salt catalyst is disclosed, comprising:

an ionic complex of i) a nitrogen base comprising one or more guanidineand/or amidine functional groups, and ii) an oxoacid comprising one ormore active acid groups, the active acid groups independently comprisinga carbonyl group (C═O), sulfoxide group (S═O), and/or a phosphonyl group(P═O) bonded to one or more active hydroxy groups; wherein a ratio ofmoles of the active hydroxy groups to moles of the guanidine and/oramidine functional groups is greater than 0 and less than 2.0; whereinthe salt catalyst is capable of catalyzing a ring opening polymerizationof a cyclic carbonyl compound.

Also disclosed is a method comprising:

reacting a mixture comprising a cyclic carbonyl monomer, a nucleophilicinitiator, an optional solvent, an optional accelerator, and a saltcatalyst, thereby forming a polymer by ring-opening polymerization,wherein the salt catalyst comprises an ionic complex of i) a nitrogenbase comprising one or more guanidine and/or amidine functional groups,and ii) an oxoacid comprising one or more active acid groups, the activeacid groups independently comprising a carbonyl group (C═O), sulfoxidegroup (S═O), and/or a phosphonyl group (P═O) bonded to one or moreactive hydroxy groups; wherein a ratio of moles of the active hydroxygroups to moles of the guanidine and/or amidine functional groups isgreater than 0 and less than 2.0.

Further disclosed is a method, comprising:

forming a mixture comprising a cyclic carbonyl monomer, a nucleophilicinitiator, an optional accelerator, an optional solvent, and an oxoacid,the oxoacid comprising one or more active acid groups, the active acidgroups independently comprising a carbonyl group (C═O), sulfoxide group(S═O), and/or a phosphonyl group (P═O) bonded to one or more activehydroxy groups; and

adding to the mixture a nitrogen base comprising one or more guanidineand/or amidine functional groups, thereby forming a salt catalyst,wherein a ratio of moles of the active hydroxy groups to moles of theguanidine and/or amidine functional groups of the salt catalyst isgreater than 0 and less than 2.0,

allowing the salt catalyst to catalyze ring opening polymerization ofthe cyclic carbonyl monomer, thereby forming a polymer.

An article is disclosed, comprising a ring opened polymer formedutilizing a salt catalyst.

The above-described and other features and advantages of the presentinvention will be appreciated and understood by those skilled in the artfrom the following detailed description, drawings, and appended claims.

BRIEF DESCRIPTION OF THE SEVERAL VIEWS OF THE DRAWINGS

In the drawings, like parts are numbered alike.

FIG. 1 is a graph showing the proton shift caused by a thiourea moleculeon either (a) a cyclic ester or (b) a linear ester.

FIGS. 2A to 2B are graphs of (A) the number average molecular weight(Mn) against time of polymerization, and (B) number average molecularweight against percent conversion for Example 13. The graphs show thatMn and PDI remain unchanged even 24 hours after complete conversionusing salt catalyst BA:DBU 1:1-m.

FIGS. 3A to 3C are molecular models showing the following structures:(A) BA/DBU 1:1-m salt, catalytically active; (B) BA/DBU 2:1-m salt,catalytically inactive; the second BA does not protonate DBUH+ at itsother nitrogen but rather the benzoate unit (BA⁻), thereby quenchingcatalytic activity; and (C) a 3D model showing nucleophilic activationof initiating alcohol (here CH₃OH) through the BA⁻ unit andelectrophilic activation of DBUH⁺ at the lactide carbonyl.

DETAILED DESCRIPTION

This invention is based on the discovery that acid-base complexes canactively and selectively catalyze ring opening polymerization (ROP) ofcyclic carbonyl monomers, while showing little or no catalytic activityfor competing unwanted side reactions (e.g., transesterification of thepolyester backbone formed by ring opening polymerization of a cyclicester). The acid-base complexes preferably comprise no metal in theirchemical formulas, and are referred to herein as salt catalysts. Thesalt catalysts comprise an adduct of i) an oxoacid comprising one ormore active hydroxy groups (e.g., carboxylic acids, sulfuric acid,monoesters of sulfuric acid, sulfonic acids, sulfinic acids, monoestersof phosphoric acid, diesters of phosphoric acid, organophosphonic acids,monoesters of organophosphonic acids, and/or organophosphinic acids),and ii) a nitrogen base comprising one or more guanidine and/or amidinefunctional groups. Herein, the term “adduct” means an ionic complex. AROP polymer prepared using a salt catalyst has a lower polydispersityindex (PDI) compared to a ROP polymer prepared under otherwise identicalreaction conditions without the oxoacid. A lower PDI indicates greaterselectivity of the salt catalyst in promoting chain growth (ringopening) compared to unwanted side reactions. The PDI and catalyticactivity can be controlled by the ratio of moles of active hydroxygroups to moles of guanidine and/or amidine functional groups in thesalt catalyst. By adjusting this ratio, the PDI can be optimized withinan acceptable range of catalytic activity. As is demonstrated by theexamples further below, excess oxoacid or a non-oxoacid (i.e., HCl) caninactivate the guanidine and/or amidine base altogether toward ROP chaingrowth and its competing side reactions. The salt catalysts makepossible a large variety of bio-degradable polymers of controlledpolydispersity and molecular weight that are suitable for a variety ofapplications including but not limited to medical and packagingapplications.

Guanidine nitrogen bases and amidine nitrogen bases are active andnon-selective catalysts for ring opening polymerizations, meaning theyexhibit poor selectivity toward catalyzing ring opening polymerizationversus unwanted side reactions. The finding that oxoacid adducts ofthese nitrogen bases have greater selectivity toward ring openingpolymerization results from the adduct itself catalyzing the ringopening reaction, as a unique catalyst composition. The disclosed saltcatalysts are not in an equilibrium with free guanidine or free amidinenitrogen base during the ring opening polymerization.

Nitrogen bases other than guanidine or amidine nitrogen bases (e.g.,4-N,N-dimethylamino pyridine (DMAP)) can also form oxoacid adducts.These nitrogen bases can also catalyze ring opening polymerization.However, the oxoacid adducts of these nitrogen bases do not catalyzering opening polymerization. With these oxoacid adducts, it is theexcess free nitrogen base in solution with the oxoacid adduct thatcatalyzes the ring opening polymerization. The presence of oxoacidmerely slows the rate of ring opening polymerization by lowering theconcentration of the free nitrogen base. When sufficient oxoacid ispresent to form an adduct with all of the nitrogen base, catalysisceases. Using otherwise identical reaction conditions, the selectivityof the oxoacid adduct containing excess free nitrogen base, as measuredby PDI, can be comparable to that of the nitrogen base alone, but yieldsand number average molecular weight of the resulting ring opened polymerare generally lower.

The disclosed salt catalysts comprise a nitrogen base having afunctional group selected from the group consisting of acyclic guanidinefunctional groups, cyclic guanidine functional groups, acyclic amidinefunctional groups, cyclic amidine functional groups, and combinationsthereof.

A guanidine functional group comprises three nitrogens attached to acentral methine carbon, as shown in formula (1):

Herein, a starred bond indicates a point of attachment to a functionalgroup. The imine group,

is not conjugated with another double bond.

When the central methine carbon of the guanidine functional groupresides outside a ring, the guanidine functional group is referred to asan acyclic guanidine functional group. Non-limiting examples of nitrogenbases comprising acyclic guanidine functional groups include2-tert-butyl-1,1,3,3-tetramethyl guanidine,2-(4-methylbenzyl)-1,1,3,3-tetramethyl guanidine,2-phenyl-1,1,3,3-tetramethylguanidine,2-hexyl-1,1,3,3-tetraethylguanidine,2-butyl-1,1,3,3-tetraethylguanidine,N,N′-(dicyclohexyl)pyrrolidine-1-carboximidamide (DCPG), andcombinations thereof. DCPG has the structure:

When the central methine carbon of the guanidine functional groupresides in a ring, the guanidine functional group is referred to as acyclic guanidine functional group. No limitation is placed on the sizeof the ring containing the cyclic guanidine functional group. Thenitrogen base can comprise fused rings, non-fused rings, or acombination thereof comprising a cyclic guanidine functional group.Non-limiting examples of nitrogen bases comprising a cyclic guanidinefunctional group include 7-methyl-1,5,7-triazabicyclo(4.4.0)dec-5-ene(MTBD) and 1,5,7-triazabicyclo(4.4.0)dec-5-ene (TBD).

An amidine functional group has two nitrogens attached to a methinecarbon as shown in formula (2):

The central imine group,

is not conjugated with another double bond.

The amidine functional group can reside in a non-cyclic structure or acyclic structure. When the central methine carbon of the amidinefunctional group resides outside a ring, the amidine functional group isreferred to as an acyclic amidine functional group. Non-limitingexamples of nitrogen bases comprising an acyclic amidine functionalgroup include N-methyl-N′,N′-diethyl benzamidine, andN-benzyl-N-phenyl-N′-p-tolyl-benzamidine. When the central methinecarbon of the amidine functional group resides in a ring, the amidinefunctional group is referred to as a cyclic amidine functional group. Nolimitation is placed on the size of the ring that partially or whollycontains the cyclic amidine functional group. The nitrogen base cancomprise fused rings, non-fused rings, or a combination thereofcomprising a cyclic amidine functional group. Non-limiting examples ofnitrogen bases that comprise a cyclic amidine functional group include1,8-diazabicyclo(5.4.0)undec-7-ene (DBU) and1,5-diazabicyclo(4.3.0)non-5-ene (DBN).

The nitrogen base can be a polymer supported guanidine and/or amidinenitrogen base (i.e., the nitrogen base is covalently bound to apolymer). In this instance, the polymer comprises one or more repeatunits comprising a side chain guanidine and/or amidine functional group.The side chain guanidine and/or amidine functional group can be a cyclicor an acyclic guanidine and/or amidine functional group. Polymersupported nitrogen bases include, for example, polystyrene bound1,5,7-triazabicyclo[4.4.0]dec-5-ene (TBD), referred to as PS-TBD,polystyrene bound 1,8-diazabicyclo(5.4.0)undec-7-ene) (DBU), referred toas PS-DBU, and polystyrene bound 1,5-diazabicyclo(4.3.0)non-5-ene (DBN),referred to as PS-DBN.

In an embodiment, the nitrogen base comprises one guanidine and/oramidine functional group. In another embodiment, the nitrogen base isselected from the group consisting of7-methyl-1,5,7-triazabicyclo(4.4.0)dec-5-ene (MTBD),1,5,7-triazabicyclo(4.4.0)dec-5-ene (TBD),1,8-diazabicyclo(5.4.0)undec-7-ene (DBU),1,5-diazabicyclo(4.3.0)non-5-ene (DBN), and combinations thereof.

The oxoacid comprises one or more active acid groups, the active acidgroups independently comprising one or more active hydroxy groups bondedto a carbonyl group (C═O), sulfoxide group (S═O), and/or a phosphonylgroup (P═O). The active hydroxy group is capable of donating a proton toform an ionic complex with the guanidine and/or amidine nitrogen base.The oxoacid can have the general formula (3):Q′

W′—OH]_(n)  (3),wherein

n is a positive integer greater than or equal to 1,

Q′ is a monovalent radical independently selected from the groupconsisting of hydroxy, C₁-C₅₀ alkoxy groups, C₁-C₅₀ aryloxy groups,C₁-C₅₀ alkyl groups, C₁-C₅₀ aryl groups, and combinations thereof, and

each W′ is a divalent linking group independently selected from thegroup consisting of:

wherein each Q″ is a monovalent radical independently selected from thegroup consisting of hydroxy groups, C₁-C₅₀ alkoxy groups, C₁-C₅₀ aryloxygroups, C₁-C₅₀ alkyl groups, C₁-C₅₀ aryl groups, and combinationsthereof. In an embodiment, n is 1, W′ is a

or a

group, and Q′ is a monovalent radical independently selected from C₁-C₅₀alkyl groups and C₁-C₅₀ aryl groups.

Exemplary oxoacids include carboxylic acids, sulfuric acid, monoestersof sulfuric acid, sulfonic acids, sulfinic acids, phosphoric acid,organophosphates (i.e., monoesters of phosphoric acid, and diesters ofphosphoric acid), phosphorous acid, organophosphonic acids, monoestersof organophosphonic acids (i.e., organophosphonates), phosphinic acid,organophosphinic acids, and combinations thereof. Sulfuric acid,phosphoric acid, and phosphorous acid have 2, 3, and 2 active hydroxygroups, respectively. Phosphinic acid has 1 active hydroxy group. Eachcarboxylic acid group, sulfonic acid group, or sulfinic acid group has 1active hydroxy group. Each phosphate functional group can have 1 or 2active hydroxy groups. Each phosphonate functional group can have 1 or 2active hydroxy groups.

Exemplary carboxylic acids include monocarboxylic acids, such as aceticacid, cyclohexane carboxylic acid, and benzoic acid (BA).Multi-functional carboxylic acids include dicarboxylic acids, such asmalonic acid, succinic acid, glutaric acid, phthalic acid, isophthalicacid, and terephthalic acid; and tricarboxylic acids, such as trimesicacid (1,3,5-benzenetricarboxylic acid). Also contemplated is the use ofoligomeric and polymeric carboxylic acids such as poly(methacrylic acid)and copolymers of methacrylic acid or acrylic acid as the oxoacid.

Exemplary sulfonic acids include methane sulfonic acid andp-toluensulfonic acid (TsOH). Also contemplated are oligomeric andpolymeric sulfonic acids such as poly(styrene sulfonic acid) and itscopolymers.

Exemplary sulfinic acids include ethanesulfinic acid, benzene sulfinicacid, 3-methoxybenzenesulfinic acid, 2,4,6-trimethyl-benzenesulfinicacid, and 2-naphthalene sulfinic acid.

Organophosphates include organophosphate monoesters of general formula(4) and organophosphate diesters of general formula (5):

wherein each R independently comprises one or more carbons. Exemplaryphosphate monoesters include methyl phosphate, phenyl phosphate, and4-(tert-pentyl)phenyl phosphate. Exemplary phosphate diesters includedimethyl phosphate, dibutyl phosphate, and diphenyl phosphate.

Organophosphonates include organophosphonic acids of general formula(6):

and organophosphonic acid monoesters of general formula (7):

wherein each R independently comprises one to fifty carbons. Exemplaryorganophosphonic acids include phenylphosphonic acid, octylphosphonicacid, and 2,3-xylyl phosphonic acid. Exemplary organophosphonic acidmonoesters include O-ethyl methylphosphonate, O-isopropylmethylphosphonate, O-pinacolyl methylphosphonate, and O-ethylphenylphosphonate.

Organophosphinic acids have the general formula (8):

wherein each R independently comprises one to fifty carbons. Exemplaryorganophosphinic acids include diphenylphosphinic acid anddimethylphosphinic acid.

In an embodiment, the oxoacid is selected from the group consisting ofcarboxylic acids, sulfonic acids, and combinations thereof. In anembodiment, the oxoacid comprises one carboxylic acid group or onesulfonic acid group.

A method of preparing a salt catalyst comprises combining an oxoacid anda nitrogen base, wherein a ratio of moles of the active hydroxy groupsof the oxoacid to moles of the guanidine and/or an amidine functionalgroups of the nitrogen base is greater than 0 and less than 2.0. Moreparticularly, the ratio of moles of the active hydroxy groups of theoxoacid to moles of the guanidine and/or an amidine functional groups ofthe nitrogen base is 0.5 to 1.5. Even more particularly, the ratio ofthe moles of active hydroxy groups of the oxoacid to moles of theguanidine and/or an amidine functional groups of the nitrogen base is0.9 to 1.5. Isolating the salt catalyst can be accomplished usingwell-established techniques, including precipitation of the saltcatalyst in a non-solvent.

Alternatively, the salt catalyst can be prepared in situ, as describedfurther below under methods of ring opening polymerization.

The salt catalyst is preferably metal-free, meaning the chemical formulaof the salt catalyst contains none of the following metals: beryllium,magnesium, calcium, strontium, barium, radium, aluminum, gallium,indium, thallium, germanium, tin, lead, arsenic, antimony, bismuth,tellurium, polonium, and metals of Groups 3 to 12 of the Periodic Table.This exclusion includes ionic and non-ionic forms of the foregoingmetals. Metals of Groups 3 to 12 of the Periodic Table include scandium,titanium, vanadium, chromium, manganese, iron, cobalt, nickel, copper,zinc, yttrium, zirconium, niobium, molybdenum, technetium, ruthenium,rhodium, palladium, silver, cadmium, lanthanum, cerium, praseodymium,neodymium, promethium, samarium, europium, gadolinium, terbium,dysprosium, holmium, erbium, thulium, ytterbium, lutetium, hafnium,tantalum, tungsten, rhenium, osmium, iridium, platinum, gold, mercury,actinium, thorium, protactinium, uranium, neptunium, plutonium,americium, curium, berkelium, californium, einsteinium, fermium,mendelevium, nobelium, lawrencium, rutherfordium, dubnium, seaborgium,bohrium, hassium, meitnerium, darmstadtium, roentgenium, andcopernicium.

Further disclosed are methods of ring opening polymerization of a cycliccarbonyl monomer utilizing a salt catalyst. ROP polymers can be preparedin high yield under mild conditions and/or in reaction times of lessthan about 48 hours, more particularly 24 hours or less, with the saltcatalysts. The resinous products are “living” polymers, capable ofundergoing chain growth in a stepwise manner using either the samecyclic carbonyl monomer or a different cyclic carbonyl monomer.

One method of ring opening polymerization comprises reacting a mixturecomprising a cyclic carbonyl monomer, a nucleophilic initiator, anoptional solvent, an optional accelerator, and a salt catalyst, therebyforming a polymer by ring-opening polymerization, wherein the saltcatalyst comprises i) an oxoacid comprising one or more active hydroxygroups, and ii) a nitrogen base comprising one or more guanidine and/oran amidine functional groups, wherein a ratio of moles of active hydroxygroups to moles of guanidine and/or amidine functional groups is greaterthan 0 and less than 2.0.

In another method of ring opening polymerization, the salt catalyst isprepared in situ. This method comprises forming a mixture comprising acyclic carbonyl monomer, a nucleophilic initiator, an optionalaccelerator, an optional solvent, and an oxoacid comprising one or moreactive hydroxy groups; adding to the mixture a nitrogen base comprisingone or more guanidine and/or amidine functional groups, wherein a ratioof moles of active hydroxy groups to moles of guanidine and/or amidinefunctional groups is greater than 0 and less than 2.0, thereby forming aring opened polymer of the cyclic carbonyl monomer.

When preparing the salt catalyst in situ, no limitation is placed on theorder of addition of the nitrogen base, the oxoacid, or the othercomponents of the reaction mixture. Another method of ring openingpolymerization comprises forming a mixture comprising a cyclic carbonylmonomer, a nucleophilic initiator, an optional accelerator, a nitrogenbase comprising one or more guanidine and/or amidine functional groups,and an oxoacid comprising one or more active hydroxy groups, wherein aratio of moles of active hydroxy groups to moles of guanidine and/oramidine functional groups is greater than 0 and less than 2.0; andadding to the mixture a solvent, thereby forming a ring opened polymerof the cyclic carbonyl monomer.

The ROP reaction mixture comprises at least one salt catalyst and, whenappropriate, several salt catalysts together. The ROP catalyst is addedin a proportion of 1/20 to 1/40,000 moles relative to moles of thecyclic carbonyl monomers, and preferably of 1/1,000 to 1/20,000 moles.

The cyclic carbonyl monomer comprises a cyclic functional group selectedfrom the group consisting of cyclic esters, cyclic carbamates, cyclicureas, cyclic thiocarbamates, cyclic thioureas, cyclic dithiocarbonates,and combinations thereof (Table 1). The cyclic carbonyl monomer cancomprise one or more of these cyclic functional groups.

TABLE 1 Cyclic ester

Cyclic carbonate

Cyclic urea

Cyclic carbamate

Cyclic thiocarbamate

Cyclic thiocarbonate

Cyclic dithiocarbonate

More specifically, the cyclic carbonyl monomer is a cyclic ester or acyclic carbonate. Exemplary cyclic esters include: L-lactide, D-lactide,DL-lactide, beta-butyrolactone, delta-valerolactone, andepsilon-caprolactone. Exemplary cyclic carbonates include trimethylenecarbonate, methyl 5-methyl-2-oxo-1,3-dioxane-5-carboxylate, and ethyl5-methyl-2-oxo-1,3-dioxane-5-carboxylate. These and other examples ofcyclic esters and cyclic carbonates are listed in Table 2. The cycliccarbonyl monomers can be used alone or in combination.

TABLE 2

  (MTCOPrCl)

  (MTCOPrBr)

  (MTCOEtI)

  (MTCOEE)

  m = 1, Trimethylene carbonate (TMC) m = 2, Tetramethylene carbonate(TEMC) m = 3, Pentamethylene carbonate (PMC)

  R = hydrogen (MTCOH) R = methyl (MTCOMe) R = t-butyl (MTCO^(t)Bu) R =ethyl (MTCOEt)

  (MTCCl)

  (MTCOBn)

  (MTCTFE)

  R = methyl R = iso-propyl

  R = H; n = 1: beta-Propiolactone (b-PL) R = H; n = 2:gamma-Butyrolactone (g-BL) R = H; n = 3: delta-Valerolactone (d-VL) R =H; n = 4: epsilon-Caprolactone (e-CL) R = CH₃; n = 1: beta-Butyrolactone(b-BL) R = CH₃; n = 2: gamma-Valerolactone (g-VL)

  Pivalolactone (PVL)

  1,5-Dioxepan-2-one (DXO)

  5-(Benzyloxy)oxepan-2-one (BXO)

  7-Oxooxepan-4-yl 2-bromo-2- methylpropanoate (BMP-XO)

  5-Phenyloxepan-2-one (PXO)

  5-Methyloxepan-2-one (MXO)

  1,4,8-Trioxa(4,6)spiro-9-undecane (TOSUO)

  5-(Benzyloxymethyl)oxepan-2-one (BOMXO)

  7-Oxooxepan-4-yl 3-hydroxy-2- (hydroxymethyl)-2-methylpropanoate(OX-BHMP)

  (Z)-6,7-Dihydrooxepin-2(3H)-one (DHXO)

  (MTCU)

  D-Lactide (DLA), L-Lactide (LLA) racemic Lactide, 1:1 D:L forms (DLLA)

  meso-Lactide, (MLA) (two opposite centers of asymmetry, R and S)

  Glycolide (GLY)

  (MTCOMPEG)

The cyclic carbonyl compounds can also bear polymerizeable functionalgroups which can be polymerized by ROP, free-radical, or otherpolymerization techniques, such as controlled radical polymerizationtechniques, including nitroxide-mediated radical polymerization, atomtransfer radical polymerization (ATRP), and reversibleaddition-fragmentation polymerization (RAFT). These cyclic carbonylmonomers can be polymerized through the cyclic carbonyl group, thepolymerizeable functional group, or both. The cyclic carbonyl group andthe polymerizeable functional group can be polymerized in any order(e.g., ROP of a cyclic carbonate and then polymerization of thefunctional group, vice versa, or simultaneously). Alternatively, thefunctional group can be polymerized (or copolymerized) to afford apolymer with pendant cyclic carbonyl groups. These cyclic carbonylgroups can then be reacted to append groups to the polymer. For example,ring-opening reactions of cyclic carbonates with primary or secondaryamines are known to produce hydroxy carbamates.

Generally, the above described cyclic carbonyl monomers can be purifiedby recrystallization from a solvent such as ethyl acetate or by otherknown methods of purification, with particular attention being paid toremoving as much water as possible from the monomer. The monomermoisture content can be from 1 to 10,000 ppm, 1 to 1,000 ppm, 1 to 500ppm, and most specifically 1 to 100 ppm, by weight of the monomer.

In a more specific embodiment, the cyclic carbonyl monomer is lactide,beta-butyrolactone, gamma-butyrolactone, gamma-valerolactone,delta-valerolactone, epsilon-caprolactone, or a combination thereof.Even more specifically, the monomer is D-lactide, L-lactide,meso-lactide (having two centers of opposite symmetry, R and S), racemicD,L-lactide (a 1:1 mixture of D and L forms), or a combinationcomprising at least one of the foregoing lactides. The ring-openingpolymerization of lactide (LA) to form polylactide (PLA), a polyester,is shown in Scheme 1 (optical centers not shown).

D-lactide, L-lactide, racemic D,L-lactide, and meso-lactide can bepolymerized using a salt catalyst to form substantially a monodispersepoly(lactide) with substantial retention of R and/or S symmetry. In thisexample, the initiator is phenol which becomes a phenoxy endgroup in thepoly(lactide) chain. A backbone fragment derived from an initiator isreferred to herein as an initiator fragment. The initiator fragment canbe an endgroup or a non-endgroup, depending on whether the initiatorcomprises one or more nucleophilic initiator groups for the ring openingpolymerization. Each initiator group can potentially initiate a ringopening polymerization, thereby forming a branched polymer structurehaving a ring opened polymer chain attached to each initiator group.

In another specific embodiment, the cyclic carbonyl monomer is selectedfrom the group consisting of trimethylene carbonate, tetramethylenecarbonate, pentamethylene carbonate, and combinations thereof.

Initiators for the ring opening polymerization generally includematerials having one or more nucleophilic groups selected from the groupconsisting of alcohols, amines, and thiols. More particularly, theinitiator is an alcohol. The alcohol initiator can be any suitablealcohol, including mono-alcohol, diol, triol, or other polyol, with theproviso that the choice of alcohol does not adversely affect thepolymerization yield, polymer molecular weight, and/or the desirablemechanical and physical properties of the resulting ROP polymer. Thealcohol can be multi-functional comprising, in addition to one or morehydroxyl groups, a halide, an ether group, an ester group, an amidegroup, or other functional group. Additional exemplary alcohols includemethanol, ethanol, propanol, butanol, pentanol, amyl alcohol, caprylalcohol, nonyl alcohol, decyl alcohol, undecyl alcohol, lauryl alcohol,tridecyl alcohol, myristyl alcohol, pentadecyl alcohol, cetyl alcohol,heptadecyl alcohol, stearyl alcohol, nonadecyl alcohol, other aliphaticsaturated alcohols, cyclopentanol, cyclohexanol, cycloheptanol,cyclooctanol, other aliphatic cyclic alcohols, phenol, substitutedphenols, benzyl alcohol, substituted benzyl alcohol, benzenedimethanol,trimethylolpropane, a saccharide, poly(ethylene glycol), propyleneglycol, alcohol functionalized block copolymers derived from oligomericalcohols, alcohol functionalized branched polymers derived from branchedalcohols, or a combination thereof. Monomeric diol initiators includeethylene glycols, propylene glycols, hydroquinones, and resorcinols. Anexample of a diol initiator is BnMPA, derived from 2,2-dimethylolpropionic acid, a precursor used in the preparation of cyclic carbonatemonomers.

As indicated above, the ROP initiator can be a polymeric alcohol. Moreparticularly, the ROP initiator can be a polyether alcohol, whichincludes but is not limited to poly(alkylene glycol)s and mono endcapped poly(alkylene glycol)s. Such initiators serve to introduce a mainchain hydrophilic first block into the resulting ROP polymer. A secondblock of the ROP polymer comprises a living chain segment formed by ringopening polymerization of a cyclic carbonyl monomer.

More specific polyether alcohols include poly(alkylene glycol)s of thegeneral formula (9):HO—[C(R⁷)₂(C(R⁷)₂)_(a′)C(R⁷)₂O]_(n)—H  (9),wherein a′ is 0 to 8, n is an integer from 2 to 10000, and each R⁷ isindependently a monovalent radical selected from the group consisting ofhydrogen, and alkyl groups of 1 to 30 carbons. Thus, the ether repeatunit comprises 2 to 10 backbone carbons between each backbone oxygen.More particularly, the poly(alkylene glycol) can be a mono end cappedpoly(alkylene glycol), represented by the formula (10):R⁸O—[C(R⁷)₂(C(R⁷)₂)_(a′)C(R⁷)₂O]_(n)—H  (10),wherein R⁸ is a monovalent hydrocarbon radical comprising 1 to 20carbons.

As non-limiting examples, the polyether alcohol can be a poly(ethyleneglycol) (PEG), having the structure HO—[CH₂CH₂O]_(n)—H, wherein theether repeat unit CH₂CH₂O (shown in the brackets) comprises two backbonecarbons linked to a backbone oxygen. The polyether alcohol can also be apolypropylene glycol) (PPG) having the structure HO—[CH₂CH(CH₃)O]_(n)H,where the ether repeat unit CH₂CH(CH₃)O comprises two backbone carbonslinked to a backbone oxygen with a methyl side-chain. An example of monoend capped PEG is the commercially available mono methyl end capped PEG(MPEG), wherein R⁸ is a methyl group. Other examples includepoly(oxetane), having the structure HO—[CH₂CH₂CH₂O]_(n)—H, andpoly(tetrahydrofuran), having the structure HO—[CH₂(CH₂)₂CH₂O]_(n)—H.

The mono end capped poly(alkylene glycol) can comprise more elaboratechemical end groups, represented by the general formula (11):Z′—[C(R⁷)₂(C(R⁷)₂)_(a′)C(R⁷)₂O]_(n-1) —H  (11),wherein Z′ is a monovalent radical including the backbone carbons andoxygen of the end repeat unit, and can have 2 to 100 carbons. Thefollowing non-limiting examples illustrate mono end-derivatization ofpoly(ethylene glycol) (PEG). As described above, one end repeat unit ofPEG can be capped with a monovalent hydrocarbon group having 1 to 20carbons, such as the mono methyl PEG (MPEG), wherein Z′ is MeOCH₂CH₂O—.The dash on the end of the MeOCH₂CH₂O— indicates the point of attachmentto the polyether chain. In another example, Z′ includes a thiol group,such as HSCH₂CH₂O—, or a thioether group, such as MeSCH₂CH₂O—. Inanother example, one end unit of PEG is an aldyhyde, wherein Z′ can beOCHCH₂CH₂O—. Treating the aldehyde with a primary amine produces animine, wherein Z′ is R⁹N═CHCH₂CH₂O—. R⁹ is a monovalent radical selectedfrom hydrogen, an alkyl group of 1 to 30 carbons, or an aryl groupcomprising 6 to 100 carbons. Continuing, the imine can be reduced to anamine, wherein Z′ is R⁹NHCH₂CH₂CH₂O—. In another example, one end repeatunit of PEG can be oxidized to a carboxylic acid, wherein Z′ isHOOCCH₂O—. Using known methods the carboxylic acid can be converted toan ester, wherein Z′ becomes R⁹OCCH₂O—. Alternatively, the carboxylicacid can be converted to an amide, wherein Z′ becomes R⁹NHOCCH₂O—. Manyother derivatives are possible. For example, Z′ can comprise abiologically active moiety that interacts with a specific cell type,more specifically a galactose moiety that specifically recognizes livercells. In this instance, Z′ has the structure:

wherein L′ is a divalent linking group comprising 2 to 50 carbons. Thestarred bond indicates the attachment point to the polyether chain. Z′can comprise other biologically active moieties such as a mannosemoiety.

The reaction mixture can include an optional additive that may improvethe selectivity and/or activity of the disclosed salt catalysts.Optional additives include weaker nitrogen bases that do not comprise aguanidine or amidine functional group. Exemplary nitrogen bases foroptional accelerators include pyridine (Py),N,N-dimethylaminocyclohexane (Me₂NCy), 4-N,N-dimethylaminopyridine(DMAP), trans 1,2-bis(dimethylamino)cyclohexane (TMCHD), (−)-sparteine,(Sp) 1,3-bis(2-propyl)-4,5-dimethylimidazol-2-ylidene (Im-1),1,3-bis(2,4,6-trimethylphenyl)imidazol-2-ylidene (Im-2),1,3-bis(2,6-di-i-propylphenyl(imidazol-2-ylidene (Im-3),1,3-bis(1-adamantyl)imidazol-2-ylidene (Im-4),1,3-di-i-propylimidazol-2-ylidene (Im-5),1,3-di-t-butylimidazol-2-ylidene (Im-6),1,3-bis(2,4,6-trimethylphenyl)-4,5-dihydroimidazol-2-ylidene (Im-7),1,3-bis(2,6-di-i-propylphenyl)-4,5-dihydroimidazol-2-ylidene,1,3-bis(2,6-di-i-propylphenyl)-4,5-dihydroimidazol-2-ylidene (Im-8) or acombination thereof, shown in Table 3.

TABLE 3

  Pyridine (Py)

  N,N-Dimethylaminocyclohexane (Me₂NCy)

  4-N,N-Dimethylaminopyridine (DMAP)

  trans 1,2-Bis(dimethylamino)cyclohexane (TMCHD)

  (−)-Sparteine (Sp)

  1,3-Bis(2-propyl)-4,5-dimethylimidazol-2-ylidene (Im-1)

  1,3-Bis(2,4,6-trimethylphenyl)imidazol-2- ylidene (Im-2)

  1,3-Bis(2,6-di-i-propylphenyl(imidazol- 2-ylidene (Im-3)

  1,3-Bis(1-adamantyl)imidazol-2-yliden) (Im-4)

  1,3-Di-i-propylimidazol-2-ylidene (Im-5)

  1,3-Di-t-butylimidazol-2-ylidene (Im-6)

  1,3-Bis(2,4,6-trimethylphenyl)-4,5- dihydroimidazol-2-ylidene (Im-7)

  1,3-Bis(2,6-di-i-propylphenyl)-4,5- dihydroimidazol-2-ylidene (Im-8)

In an embodiment, the optional additive is a weak nitrogen base otherthan a guanidine or amidine nitrogen base, the weak nitrogen base havingtwo or three nitrogens, each capable of participating as a Lewis base.Exemplary additive nitrogen bases include (−)-sparteine or DMAP.

The ring-opening polymerization can be performed with or without the useof a solvent, more particularly with a solvent. Optional solventsinclude dichloromethane, chloroform, benzene, toluene, xylene,chlorobenzene, dichlorobenzene, benzotrifluoride, petroleum ether,acetonitrile, pentane, hexane, heptane, 2,2,4-trimethylpentane,cyclohexane, diethyl ether, t-butyl methyl ether, diisopropyl ether,dioxane, tetrahydrofuran, or a combination comprising one of theforegoing solvents. When a solvent is present, a suitable cycliccarbonyl monomer concentration is about 0.1 to 5 moles per liter, andmore particularly about 0.2 to 4 moles per liter. In an embodiment, thereaction mixture for the ring-opening polymerization contains nosolvent.

The polymerization can be performed at a temperature that is aboutambient temperature or higher, more specifically a temperature from 15°C. to 200° C., and more particularly 20° C. to 200° C. When the reactionis conducted in bulk, the polymerization is performed at a temperatureof 50° C. or higher, and more particularly 100° C. to 200° C. Reactiontimes vary with solvent, temperature, agitation rate, pressure, andequipment, but in general the polymerizations are complete within 1 to100 hours.

Whether performed in solution or in bulk, the polymerizations areconducted in an inert (i.e., dry) atmosphere and at a pressure of from100 to 500 MPa (1 to 5 atm), more typically at a pressure of 100 to 200MPa (1 to 2 atm). At the completion of the reaction, the solvent can beremoved using reduced pressure.

The salt catalyst is present in an amount of about 0.2 to 20 mol %, 0.5to 10 mol %, 1 to 5 mol %, or 1 to 2.5 mol %, based on moles of thecyclic carbonyl monomer.

The optional accelerator, when present, is present in an amount of 0.1to 5.0 mol %, 0.1 to 2.5 mol %, 0.1 to 1.0 mol %, or more particularly0.2 to 0.5 mol %, based on moles of the cyclic carbonyl monomer.

The amount of initiator is calculated based on the equivalent molecularweight per nucleophilic initiator group in the initiator. Thenucleophilic initiator groups are present in an amount of 0.001 to 10.0mol %, 0.1 to 2.5 mol %, 0.1 to 1.0 mol %, and 0.2 to 0.5 mol %, basedon moles of cyclic carbonyl functional groups capable of undergoing ringopening polymerization. For example, if the molecular weight of theinitiator is 100 g/mole and the initiator has 2 nucleophilic initiatorgroups, the equivalent molecular weight per nucleophilic initiator groupis 50 g/mole. If the polymerization calls for 5 mol % nucleophilicinitiator groups per mole of the cyclic carbonyl monomer, the amount ofinitiator is 0.05×50=2.5 g per mole of cyclic carbonyl monomer.

In a specific embodiment, the salt catalyst is present in an amount ofabout 0.2 to 20 mol % based on moles of cyclic carbonyl monomer, and thenucleophilic initiator groups are present in an amount of 0.1 to 5.0 mol% based on moles of cyclic carbonyl monomer.

If a cyclic carbonyl comonomer comprising additional nucleophilic groups(e.g., OX-BHMP) is used in the preparation of the ROP polymer, thenthese additional nucleophilic groups can serve as initiator groups forROP polymer chain growth. If the additional nucleophilic groups onlyserve as initiator groups, the result can be a ROP polymer having abranched, hyperbranched, comb, bottlebrush, or other such structure. Ifthe reaction conditions permit, the additional nucleophilic groups canpotentially also react with active side chain groups of non-reactedcyclic carbonate monomers or active side chain groups of the samepolymer chain (i.e., an intramolecular reaction) or another polymerchain (i.e., an intermolecular reaction). Intramolecular reactions canproduce cyclic structures, while intermolecular reactions can afford apolymeric crosslinked network or gel.

In an embodiment, the ring opening polymerization proceeds withsubstantially no intramolecular reaction of a polymer chain to form acyclic structure, or intermolecular reaction with another polymer chain,which can result in a branched structure. The ring opened polymer is alinear polymer having controlled polydispersity.

Also disclosed are the ROP polymers formed by the above describedmethods utilizing a salt catalyst. The polymers have a number-averagemolecular weight, Mn, as determined by size exclusion chromatography, ofpreferably at least 1000 g/mol, more preferably 4000 g/mol to 150000g/mol, and even more preferably 10000 g/mol to 50000 g/mol. The polymersalso have preferably a narrow polydispersity index (PDI), generally 1.01to 1.30, and more preferably 1.01 to 1.20. In an embodiment, thepolydispersity index is 1.0 to 1.10.

The ROP polymer comprises an initiator fragment comprising at least oneoxygen, nitrogen, and/or sulfur backbone heteroatom, which is derivedfrom the alcohol, amine, or thiol nucleophilic initiator group. Thebackbone heteroatom is linked to a first repeat unit of the ROP polymerchain grown therefrom.

The ROP polymer further comprises a backbone structure selected from thegroup consisting of polyesters, polycarbonates, polyureas,polycarbamates, polythiocarbamates, polythiocarbonates, andpolydithiocarbonates, formed by the ring opening polymerization ofcyclic esters, cyclic ureas, cyclic carbamates, cyclic thiocarbamates,cyclic thiocarbonates, and cyclic dithiocarbonates, respectively. Thesebackbone structures are listed in Table 4.

TABLE 4 Polyester

Polycarbonate

Polyurea

Polycarbamate

Polythiocarbamate

Polythiocarbonate

Polydithiocarbonate

The ROP polymer further comprises a living end unit capable ofinitiating a ring opening polymerization of another cyclic carbonylmonomer. The living end unit comprises a nucleophilic group selectedfrom the group consisting of hydroxy groups, primary amines, secondaryamines, and thiol groups. The living end unit can be blocked (i.e.,capped) in order to impart stability to the ROP polymer.

The ROP polymer can be a homopolymer, random copolymer, an alternatingcopolymer, a gradient copolymer, or a block copolymer. The ROP polymercan comprise a linear polymer, a cyclic polymer, a graft copolymer, andother polymer topologies. Block copolymerization may be achieved bysequentially polymerizing different cyclic carbonyl monomers or bysimultaneously copolymerizing monomers with the appropriate reactivityratios. The ROP polymer can comprise hydrophilic repeat units,hydrophobic repeat units, and combinations thereof, thereby impartingamphiphilic properties to first ROP polymer.

In one embodiment the ROP polymer is a polyester, polyester copolymer, apolycarbonate, a polycarbonate copolymer, or a polyester-polycarbonatecopolymer. In another embodiment, the ROP polymer has a backbonecomprising a polycarbonate homopolymer, a random polycarbonatecopolymer, or a random polyestercarbonate copolymer.

The ROP polymer can have different tacticities. Isotactic, atactic, andsyndiotactic forms of the polymers can be produced that depend on thecyclic carbonyl monomer(s), its isomeric purity, and the polymerizationconditions. In an embodiment the ROP polymer is isotactic, atactic, orsyndiotactic polylactide.

The ROP polymer can comprise residual salt catalyst in an amount lessthan 5 wt. %, less than 1 wt. %, less than 0.5 wt. %, or about 0 wt. %(i.e., an indetectable amount) based on the total weight of the ROPpolymer. The salt catalyst can be removed, if desired, by selectiveprecipitation of the ROP polymer, extraction, diafiltration, or othermethod suitable for removing a salt from a polymer. The need to removethe salt catalyst, and to what extent, can depend on the desiredproperties of the ROP polymers and the degree to which the salt catalystadversely influences those properties. Exemplary properties includesurface properties, mechanical properties, adhesion properties, andhydrolytic aging properties of the ROP polymer. Potentially, the saltcatalyst can also favorably influence one or more mechanical and/orphysical properties of the ROP polymer.

The ROP polymers comprise minimal metal contaminant when produced by asalt catalyst. In preferred embodiments, the ROP polymer contains nomore than 1000 ppm (parts per million), preferably no more than 100 ppm,more preferably no more than 10 ppm, and still more preferably no morethan 1 ppm, of every individual metal of the group consisting ofberyllium, magnesium, calcium, strontium, barium, radium, aluminum,gallium, indium, thallium, germanium, tin, lead, arsenic, antimony,bismuth, tellurium, polonium, and metals of Groups 3 to 12 of thePeriodic Table. For example, if the limit is no more than 100 ppm, theneach of the foregoing metals has a concentration not exceeding 100 ppmin the ROP polymer. When an individual metal concentration is belowdetection capability or has a concentration of zero parts, theconcentration is expressed as 0 ppm. In another embodiment, everyindividual metal of the group consisting of beryllium, magnesium,calcium, strontium, barium, radium, aluminum, gallium, indium, thallium,germanium, tin, lead, arsenic, antimony, bismuth, tellurium, polonium,and metals of Groups 3 to 12 of the Periodic Table has a concentrationof 0 ppm to 1000 ppm, 0 ppm to 500 ppm, 0 ppm to 100 ppm, 0 ppm to 10ppm, or even more particularly 0 ppm to 1 ppm in the ROP polymer. Forexample, if the concentration can have a value in the range of 0 ppm to100 ppm (inclusive), then each of the foregoing metals has aconcentration of 0 ppm to 100 ppm in the ROP polymer. In anotherembodiment, the ROP polymer comprises less than 1 ppm of everyindividual metal of the group consisting of beryllium, magnesium,calcium, strontium, barium, radium, aluminum, gallium, indium, thallium,germanium, tin, lead, arsenic, antimony, bismuth, tellurium, polonium,and metals of Groups 3 to 12 of the Periodic Table. To be clear, if thelimit is less than 1 ppm, then each of the foregoing metals has aconcentration of less than 1 ppm in the ROP polymer.

Further disclosed are articles comprising the ROP polymers formed by theabove described methods using a salt catalyst.

The ROP polymers can be applied to conventional molding methods such ascompression molding, extrusion molding, injection molding, hollowmolding and vacuum molding, and can be converted to molded articles suchas various parts, receptacles, materials, tools, films, sheets andfibers. A molding composition can be prepared comprising the polymer andvarious additives, including for example nucleating agents, pigments,dyes, heat-resisting agents, antioxidants, weather-resisting agents,lubricants, antistatic agents, stabilizers, fillers, strengthenedmaterials, fire retardants, plasticizers, and other polymers. Generally,the molding compositions comprise 30 wt. % to 100 wt. % or more of thepolymer based on total weight of the molding composition. Moreparticularly, the molding composition comprises 50 wt. % to 100 wt. % ofthe polymer.

The ROP polymer can also be formed into free-standing or supported filmsby known methods. Non-limiting methods to form supported films includedip coating, spin coating, spray coating, doctor blading. Generally,such coating compositions comprise 0.01 wt. % to 90 wt. % of the polymerbased on total weight of the coating composition. The coatingcompositions generally also include a suitable solvent necessary todissolve the ROP polymer. The coating compositions can also furtherinclude other additives selected so as to optimize desirable properties,such as optical, mechanical, and/or aging properties of the films.Non-limiting examples of additives include surfactants, ultravioletlight absorbing dyes, heat stabilizers, visible light absorbing dyes,quenchers, particulate fillers, and flame retardants. Combinations ofadditives can also be employed.

With the proper hydrophilic-hydrophobic balance, the ROP polymer canalso potentially form micelle dispersions in water useful as drugdelivery vehicles, anti-microbial agents, and/or gene carriers.

The following examples further illustrate the use of the salt catalystsfor ring opening polymerizations.

EXAMPLES

Materials used in the following examples are listed in Table 5.

TABLE 5 Abbreviation Description Supplier MTDB 7-Methyl-1,5,7- SigmaAldrich triazabicyclo[4.4.0]dec-5-ene DBU1,8-Diazabicyclo(5.4.0)undec-7-ene Sigma Aldrich DBN1,5-Diazabicyclo(4.3.0)non-5-ene Sigma Aldrich TBD1,5,7-Triazabicyclo(4.4.0)dec-5-ene Sigma Aldrich BnOH Benzyl AlcoholSigma Aldrich BA Benzoic Acid Sigma Aldrich PPh₃ TriphenylphosphineSigma Aldrich DCM Dichloromethane Sigma Aldrich DCPGN,N′-(dicyclohexyl)pyrrolidine-1- IBM carboximidamide, an acyclicguanidine DCC Dicyclohexylcarbodiimide Sigma Aldrich PS-TBD PolystyreneBound 1,5,7- Sigma Aldrich triazabicyclo[4.4.0]dec-5-ene TsOHp-Toluenesulfonic acid Sigma Aldrich

All polymerizations were carried out in a nitrogen filled glove box atroom temperature. The lactide polymerizations were carried out usingbenzyl alcohol as an initiator in 2M dichloromethane (DCM). Themonomer:initiator:nitrogen base mole ratio for all polymerization was100:1:1. Percent conversion was determined by NMR using residualmonomer. Number average molecular weight, Mn, and polydispersity index(PDI) were determined using size exclusion chromatography (SEC) relativeto polystyrene standards.

Preparation of acyclic guanidineN,N′-(dicyclohexyl)pyrrolidine-1-carboximidamide (DCPG)

Dicyclohexylcarbodiimide (DCC) was reacted neat at elevated temperaturewith one equivalent of pyrrolidine. Once the DCC melted, a homogeneoussolution was formed, and the reaction was allowed to proceed overnightto generate a viscous oil/gel. GC/MS results showed that quantitativeconversion of starting material to acyclic guanidine DCPG wasaccomplished in about 12 hours. DCPG was purified by Kugelrohrdistillation.

The Examples that follow include inventive and comparative examples.Comparative examples are indicated by a “C” after the example number.

Examples 1, 2, 3C, 4C, 5C, 6C, 7C, 8, 9, 10, and 11C Preparation of SaltCatalysts Example 1 (BA/DBU 1:1-m)

A flame dried flask was charged with benzoic acid (1.0 g, 8.18 mmol),ether (20 mL) and a stirbar under dry nitrogen atmosphere. To thestirred solution, DBU (1.2 g, 8.18 mmol) was added. Instantly, a whiteprecipitate formed and stirring was continued for 1 hour. Theprecipitate, 2.1 g (95%) of a white salt, was then washed with excessether and isolated by decantation. The salt catalyst was then driedunder high vacuum.

Example 2 (BA/MTBD 1:1-m)

A flame dried flask was charged with benzoic acid (1.0 g, 8.18 mmol),ether (20 mL) and a stirbar under dry nitrogen atmosphere. To thestirred solution, MTBD (1.2 g, 8.18 mmol) was added. Instantly, a whiteprecipitate formed and stirring was continued for 1 hour. Theprecipitate, 2.0 g (91%) of white salt, was then washed with excessether and isolated by decantation. The salt was then dried under highvacuum.

Example 3C (BA/DMAP 1:1-m)

A flame dried flask was charged with benzoic acid (1.0 g, 8.18 mmol),ether (20 mL) and a stirbar under dry nitrogen atmosphere. To thestirred solution, DMAP (1.0 g, 8.18 mmol) was added. Instantly, a whiteprecipitate formed and stirring was continued for 1 hour. Theprecipitate, 1.9 g (95%) of white salt, was then washed with excessether and isolated by decantation. The salt was then dried under highvacuum.

Example 4C (BA/N-Methylimidazole 1:1-m)

A flame dried flask was charged with benzoic acid (1.0 g, 8.18 mmol),ether (20 mL) and a stirbar under dry nitrogen atmosphere. To thestirred solution, N-methylimidazole (0.67 g, 8.18 mmol) was added.Instantly, a white precipitate formed and stirring was continued for 1hour. The precipitate, 1.5 g (90%) of white salt, was then washed withexcess ether and isolated by decantation. The salt was then dried underhigh vacuum.

Example 5C (BA/Triethylamine 1:1-m)

A flame dried flask was charged with benzoic acid (1.0 g, 8.18 mmol),ether (20 mL) and a stirbar under dry nitrogen atmosphere. To thestirred solution N-methylimidazole (0.83 g, 8.18 mmol) was added.Instantly, a white precipitate formed and stirring was continued for 1hour. The precipitate, 1.7 g (93%) of white salt, was then washed withexcess ether and isolated by decantation. The salt was then dried underhigh vacuum.

Example 6C (HCl/DBU 1:1-m)

A flame dried flask was charged with DBU (1.0 g, 6.56 mmol), ether (20mL) and a stirbar under dry nitrogen atmosphere. With vigorous stirring,a 1M ethereal HCl solution (6.6 mL, 6.6 mmol) was added to form a whiteprecipitate. Stirring was continued for 1 hour then excess solvent wasdecanted to yield 1.1 g (90%). The salt was then dried under highvacuum.

Example 7C (HCl/MTBD 1:1-m)

A flame dried flask was charged with MTBD (0.25 g, 1.63 mmol), ether (10mL) and a stirbar under dry nitrogen atmosphere. With vigorous stirringa 1M ethereal HCl solution (1.6 mL) was then added to form a whiteprecipitate. Stirring was continued for 1 hour then excess solvent wasdecanted to yield 0.29 g (94%). The salt was then dried under highvacuum.

Example 8 (TsOH/DBU 1:1-m)

A flame dried flask was charged with TsOH (1.0 g, 5.81 mmol), ether (20mL) and a stirbar under dry nitrogen atmosphere. To the stirredsolution, DBU (0.88 g, 5.81 mmol) was added. Instantly, a whiteprecipitate formed and stirring was continued for 1 hour. Theprecipitate, 1.5 g (81%) of white salt, was then washed with excessether and isolated by decantation. The salt was then dried under highvacuum.

Example 9 (TsOH/MTBD 1:1-m)

A flame dried flask was charged with TsOH (0.28 g, 1.63 mmol), ether (20mL) and a stirbar under dry nitrogen atmosphere. To the stirredsolution, MTBD (0.25 g, 1.63 mmol) was added. Instantly, a whiteprecipitate formed and stirring was continued for 1 hour. Theprecipitate, 0.47 g (88%) of white salt, was then washed with excessether and isolated by decantation. The salt was then dried under highvacuum.

Example 10 (BA/DCPG 1:1-m)

A flame dried flask was charged with BA (0.20 g, 1.63 mmol), ether (20mL) and a stirbar under dry nitrogen atmosphere. To the stirredsolution, DCPG (0.45 g, 1.63 mmol) was added. Instantly a whiteprecipitate formed and stirring was continued for 1 hour. Theprecipitate, 0.38 g (84%) of white salt, was then washed with excessether and isolated by decantation. The salt was then dried under highvacuum.

Example 11C (BA/PPh₃ 1:1-m)

A flame dried flask was charged with BA (0.20 g, 1.63 mmol), ether (20mL) and a stirbar under dry nitrogen atmosphere. To the stirredsolution, triphenylphosphine (PPH₃) (0.43 g, 1.63 mmol) was added.Instantly a white precipitate formed and stirring was continued for 1hour. The precipitate, 0.62 g (98%) of white salt, was then washed withexcess ether and isolated by decantation. The salt was then dried underhigh vacuum.

Examples 12, 13, and 14 Lactide Polymerization, Concentration SeriesUsing BA:DBU 1:1-m Example 12 (BA/DBU 1:1-m, 1M L-Lactide)

In a nitrogen filled glovebox a vial was charged with benzyl alcohol(BnOH) (3.6 microliters, 0.0347 mmol), (L)-lactide (0.50 g, 3.47 mmol),salt catalyst (Example 1) (0.010 g, 0.0347 mmol) and a stirbar. Thepolymerization was then initiated by the addition of dichloromethane(DCM) (3.5 mL). After 20 hours complete monomer consumption wasobserved. The resultant mixture was then precipitated into cold2-propanol yielding 0.35 g (71%) of white polymer, Mn 18100, PDI 1.07.

Example 13 (BA/DBU 1:1-m, 2M L-Lactide)

In a nitrogen filled glovebox a vial was charged with benzyl alcohol(3.6 microliters, 0.0347 mmol), (L)-lactide (0.50 g, 3.47 mmol), saltcatalyst (Example 1) (0.010 g, 0.0347 mmol) and a stirbar. Thepolymerization was then initiated by the addition of DCM (1.75 mL).After 24 hours complete monomer consumption was observed the resultantmixture was then precipitated into cold 2-propanol yielding 0.39 g (78%)of white polymer, Mn 17900, PDI 1.08.

Example 14 (BA/DBU 1:1-m, 4M L-Lactide)

In a nitrogen filled glovebox a vial was charged with benzyl alcohol(3.6 microliters, 0.0347 mmol), (L)-lactide (0.50 g, 3.47 mmol), saltcatalyst (Example 1) (0.010 g, 0.0347 mmol) and a stirbar. Thepolymerization was then initiated by the addition of DCM (0.9 mL). After12 hours complete monomer consumption was observed the resultant mixturewas then precipitated into cold 2-propanol yielding 0.40 g (80%) ofwhite polymer, Mn 18700, PDI 1.08.

Summarizing Examples 12 to 14, the ring opening polymerization oflactide was conducted at a concentration of 1M, 2M and 4M at ambienttemperature in DCM using BA:DBU 1:1-m (Example 1) as catalyst. Thepolymer products were precipitated in cold 2-propanol after 48 hours, 24hours, and 12 hours in yields of 71%, 78%, and 80% respectively. Mn andPDI of the polymer products were about the same, indicating that theslower polymerization rates observed when more than 1 molar equivalentof BA is present in the catalyst can be compensated for by increasingthe concentration of the polymerization reaction mixture, withoutadversely affecting PDI.

Examples 15, 16, 17, 18, and 19 Lactide Polymerization, Oxoacid andNitrogen Base Variations Example 15

Lactide polymerization with in situ generated BA/DBU 1:1-m catalyst (2ML-Lactide). In a nitrogen filled glovebox a vial was charged with benzylalcohol (3.6 microliters, 0.0347 mmol), (L)-lactide (0.50 g, 3.47 mmol),benzoic acid (4.2 mg, 0.0347 mmol), DCM (1.75 mL) and a stirbar. Thepolymerization was then initiated by the addition of DBU (5.2microliters, 0.0347 mmol). After 12 hours complete monomer consumptionwas observed. The resultant mixture was then precipitated into cold2-propanol yielding 0.41 g (82%) of white polymer, Mn 18200, PDI 1.07.This example demonstrates that the salt catalyst can be prepared insitu. The Mn and PDI are comparable to the ring opened polymer formed inExample 12 using the ex situ generated salt catalyst.

Example 16

Lactide polymerization with TsOH/DBU 1:1-m (2M L-Lactide).p-Toluenesulfonic acid (TsOH) was used because of the similarity of theresonance based acidity of both carboxylic and sulfonic acids. Thepolymerization was run at room temperature in 2M DCM with amonomer:initiator:catalyst ratio of 100:1:1-m. In a nitrogen filledglovebox a vial was charged with benzyl alcohol (3.6 microliters, 0.0347mmol), (L)-lactide (0.50 g, 3.47 mmol), salt catalyst (Example 8) (0.011g, 0.0347 mmol) and a stirbar. The polymerization was then initiated bythe addition of DCM (1.75 mL). After 24 hours complete monomerconsumption was observed. The resultant mixture was then precipitatedinto cold 2-propanol yielding yielding 0.42 (84%) of polymer Mn 18300,PDI 1.09, supporting the theory of hydroxyl group activation by theconjugate base of the acid. Compare with Examples 20C and 21C belowusing HCl, which produced no polymer.

Example 17

Lactide polymerization with BA/MTBD 1:1-m (2M L-Lactide). In a nitrogenfilled glovebox a vial was charged with benzyl alcohol (3.6 microliters,0.0347 mmol), (L)-lactide (0.50 g, 3.47 mmol), salt catalyst (Example 2)(0.010 g, 0.0347 mmol), and a stirbar. The polymerization was theninitiated by the addition of DCM (1.75 mL). After 16 hours completemonomer consumption was observed. The resultant mixture was thenprecipitated into cold 2-propanol yielding 0.40 g (80%) of whitepolymer, Mn 17900, PDI 1.08.

Example 18

Lactide polymerization with TsOH/MTBD 1:1-m (2M L-Lactide). In anitrogen filled glovebox a vial was charged with benzyl alcohol (3.6microliters, 0.0347 mmol), (L)-lactide (0.50 g, 3.47 mmol), saltcatalyst (Example 9) (0.011 g, 0.0347 mmol), and a stirbar. Thepolymerization was then initiated by the addition of DCM (1.75 mL).After 24 hours complete monomer consumption was observed. The resultantmixture was then precipitated into cold 2-propanol yielding 0.41 g (82%)of 18500 and PDI 1.08, again supporting the theory of hydroxyl groupactivation by the conjugate base of the acid (see also Example 16, andcompare with Examples 20C and 21C below with HCL, which produced nopolymer).

Example 19

Lactide polymerization with in situ generated polymer supported saltcatalyst BA/PS-TBD 1:1-m (2M L-Lactide), from poly(styrene) supportedTBD (PS-TBD). In a nitrogen filled glovebox a vial was charged withbenzyl alcohol (3.6 microliters, 0.0347 mmol), (L)-lactide (0.50 g, 3.47mmol), PS-TBD (0.0067 g, 0.0174 mmol, 0.0347 mmol), benzoic acid (0.0021g, 0.0174 mmol) and a stirbar. The polymerization was then initiated bythe addition of DCM (0.87 mL). After 148 hours, 37% conversion ofLactide to poly(Lactide) was observed; Mn 5600, PDI 1.02.

Examples 20C and 21C Lactide Polymerizations with HCl Salt Catalysts

The following polymerizations were run at room temperature in 2M DCMwith a cyclic carbonyl monomer:initiator:salt catalyst mole ratio of100:1:1.

Example 20C (HCl/DBU, 2M L-Lactide)

In a nitrogen filled glovebox a vial was charged with benzyl alcohol(1.8 microliters, 0.0173 mmol), (L)-lactide (0.25 g, 1.73 mmol), saltcatalyst (Example 6C) (0.0031 g, 0.0173 mmol) and a stirbar. Thepolymerization was then initiated by the addition of DCM (1.75 mL).After 48 hours no polymer was observed.

Example 21C (HCl/MTBD, 2M L-Lactide)

In a nitrogen filled glovebox a vial was charged with benzyl alcohol(1.8 microliters, 0.0173 mmol), (L)-lactide (0.25 g, 1.73 mmol), saltcatalyst (Example 7C) (0.0031 g, 0.0173 mmol) and a stirbar. Thepolymerization was then initiated by the addition of DCM (1.75 mL).After 48 hours no polymer was observed.

Examples 22C, 23C, 24C, 25, 26C, 27C, 28C, 29C, 30C LactidePolymerization with Salt Catalysts Made from DMAP, Methylimidazole,Triethylamine, DCPG, and Phosphine Example 22C (BA/DMAP 1:1-m, 2ML-Lactide)

In a nitrogen filled glovebox a vial was charged with benzyl alcohol(1.8 microliters, 0.0173 mmol), (L)-lactide (0.25 g, 1.73 mmol), saltcatalyst (Example 3C) (0.0042 g, 0.0173 mmol) and a stirbar. Thepolymerization was then initiated by the addition of DCM (1.75 mL).After 48 hours no polymer was observed.

Example 23C (BA/N-Methylimidazole 1:1-m, 2M L-Lactide)

In a nitrogen filled glovebox a vial was charged with benzyl alcohol(1.8 microliters, 0.0173 mmol), (L)-lactide (0.25 g, 1.73 mmol), saltcatalyst (Example 4C) (0.0035 g, 0.0173 mmol) and a stirbar. Thepolymerization was then initiated by the addition of DCM (1.75 mL).After 48 hours no polymer was observed.

Example 24C (BA/Triethylamine 1:1-m, 2M L-Lactide)

In a nitrogen filled glovebox a vial was charged with benzyl alcohol(1.8 microliters, 0.0173 mmol), (L)-lactide (0.25 g, 1.73 mmol), saltcatalyst (Example 5C) (0.0039 g, 0.0173 mmol) and a stirbar. Thepolymerization was then initiated by the addition of DCM (1.75 mL).After 48 hours no polymer was observed.

Example 25 (BA/DCPG 1:1-m, 2M L-Lactide)

In a nitrogen filled glovebox a vial was charged with benzyl alcohol(1.8 microliters, 0.0173 mmol), (L)-lactide (0.25 g, 1.73 mmol), saltcatalyst (Example 10) (0.0069 g, 0.0173 mmol), and a stirbar. Thepolymerization was then initiated by the addition of DCM (1.75 mL).After 21 hours complete monomer consumption was observed. The resultantmixture was then precipitated into cold 2-propanol yielding 0.18 g (71%)of poly(L-Lactide); Mn 16000, PDI 1.2

Example 26C (BA/PPh₃ 1:1-m, 2M L-Lactide)

In a nitrogen filled glovebox a vial was charged with benzyl alcohol(1.8 microliters, 0.0173 mmol), (L)-lactide (0.25 g, 1.73 mmol), saltcatalyst (Example 11C) (0.0066 g, 0.0173 mmol), and a stirbar. Thepolymerization was then initiated by the addition of DCM (1.75 mL).After 48 hours no polymer was observed.

Example 27C (BA/DMAP 0.5:1-m, 2M L-Lactide)

In a nitrogen filled glovebox a vial was charged with benzyl alcohol(1.8 microliters, 0.0173 mmol), (L)-lactide (0.25 g, 1.73 mmol), saltcatalyst (formed by the method of Example 3C using 0.5 mole equivalentsBA per mole of DMAP) (0.0042 g, 0.0173 mmol) and a stirbar. Thepolymerization was then initiated by the addition of DCM (1.75 mL).After 72 hours 35% conversion to polymer was observed. Mn 4600, PDI1.04. In this example, the free DMAP is the catalyst, not the adduct.

Example 28C (BA/N-Methylimidazole 0.5:1-m, 2M L-Lactide)

In a nitrogen filled glovebox a vial was charged with benzyl alcohol(1.8 microliters, 0.0173 mmol), (L)-lactide (0.25 g, 1.73 mmol), saltcatalyst (formed by the method of Example 4C using 0.5 mole equivalentsBA per mole of N-methylimidazole) (0.0035 g, 0.0173 mmol) and a stirbar.The polymerization was then initiated by the addition of DCM (1.75 mL).After 72 hours no polymer was observed.

Example 29C (BA/Triethylamine 0.5:1-m, 2M L-Lactide)

In a nitrogen filled glovebox a vial was charged with benzyl alcohol(1.8 microliters, 0.0173 mmol), (L)-lactide (0.25 g, 1.73 mmol), saltcatalyst (formed by the method of Example 5C using 0.5 mole equivalentsBA per mole of triethylamine) (0.0039 g, 0.0173 mmol) and a stirbar. Thepolymerization was then initiated by the addition of DCM (1.75 mL).After 72 hours no polymer was observed.

Example 30C (BA/PPh₃ 0.5:1-m, 2M L-Lactide)

In a nitrogen filled glovebox a vial was charged with benzyl alcohol(1.8 microliters, 0.0173 mmol), (L)-lactide (0.25 g, 1.73 mmol), saltcatalyst (formed by the method of Example 11C using 0.5 mole equivalentsBA per mole of PPh₃) (0.0066 g, 0.0173 mmol), and a stirbar. Thepolymerization was then initiated by the addition of DCM (1.75 mL).After 72 hours no polymer was observed.

Examples 31C, 32C, 33, 34, 35C, and 36C Polymerization of LactideCatalyzed by BA:DBU. BA:DBU Mole Ratio Variations

Ring opening polymerization of lactide was conducted in dichloromethane(DCM) at room temperature (RT), using the BA:DBU salt catalyst atseveral BA:DBU molar ratios. Benzyl alcohol (BnOH) was the initiator.The optimization of the salt composition began with two controlreactions used to test for the upper and lower limits of catalystactivity. First, the polymerization was performed without any BA todetermine the baseline effects of DBU as a catalyst (Table 6, Example31C). This experiment was then repeated utilizing DBU saturated with 2molar equivalents of BA (Table 6, Example 35C. The saturation point ofDBU was determined by the addition of DBU to 2M ethereal solution of BA.The precipitate was found to complex two equivalents of BA (see FIG.3B). Another control reaction (Table 6, Example 36C) was run withoutDBU, using 5 equivalents of BA relative to the initiating benzylalcohol. This control showed that BA alone does not catalyze lactidepolymerization.

TABLE 6 BA Converison M_(n) Example (Mole Equivalents) Time (%) (kDa)PDI 31C 0   30 s 100 17.4 1.6 32C 0.5 20 min 100 17.7 1.5 33  1.0 24hours 100 19 1.06 34  1.5 48 hours 30 6.8 1.07 35C 2.0 48 hours 0 N/AN/A 36C 5 equivalents BA; 48 hours 0 N/A N/A no DBU

As summarized in Table 6, the polymerization without BA was extremelyrapid and exhibited little to no control (Example 31C), whereas thepolymerization using DBU saturated with 2 molar equivalents of BA showedno activity after 48 hours (Example 35C). Several polymerizations werethen set up under identical conditions systematically varying the BAmolar concentration. Reaction times were limited to 48 hours for thepurpose of efficiency. The relationship between mole equivalents of BAper mole of DBU and reaction time can be clearly seen in Table 6. As themole equivalents of BA increases, the reaction time also increases. ThePDI is lowest (desirable) for BA levels between 0.5 and 2.0 molarequivalents (Example 33 and Example 34). On the other hand, reactiontimes exceed 24 hours at BA loadings of more than 1.0 molar equivalent(Example 34). Mn and % conversion, measured at 48 hour reaction times,also decrease as the BA loadings increase above 1.0 mole equivalent.From these results it can be reasoned that selectivity of the saltcomplex for chain growth improves up to 1.0 equivalent BA per mole ofDBU. Above 1.0 equivalents of BA, the selectivity remains constant andthe catalytic activity gradually decreases, until at 2.0 molarequivalents of BA, catalytic activity ceases.

Examples 37C, 38C, 39, 40, and 41C Poly(Lactide) (PLA) BackboneTransesterification Reactions

In Examples 37C, 38C, 39, 40, and 41C a pre-formed poly(lactide) ofknown Mn and PDI (18.8 kDa and PDI of 1.06) was subjected to thereaction conditions used in Examples 31C, 32C, 33, 34, and 35C of Table6 (above) in order to test whether the presence of BA preferentiallysuppresses transesterification side reactions relative to chain growth.The reactions were run in DCM at 2M with respect to the polymericmonomer units. The monomer:catalyst:initiator molar ratio was derivedvia NMR from the polymer, and was determined to be approximately100:1:1.

Example 37C (DBU, 2M PLA)

In a nitrogen filled glovebox a vial was charged with PLA (0.1 g, Mn18100, PDI 1.06), DCM (0.8 mL) and a stirbar. The depolymerization wasthen initiated by the addition of DBU (0.0026 g, 0.0173 mmol). After 24and 48 hours aliquots were removed and examined by GPC. After 24 hoursthe Mn/PDI was found to be 9500/1.8. Thus, DBU alone actively causestransesterification of the poly(lactide) backbone.

Example 38C (0.50 eq. BA/DBU, 2M PLA)

In a nitrogen filled glovebox a vial was charged with PLA (0.1 g, Mn18100, PDI 1.06), DCM (0.8 mL), BA (0.0010 g, 0.00865 mmol), and astirbar. The depolymerization was then initiated by the addition of DBU(0.0026 g, 0.0173 mmol). After 24 and 48 hours aliquots were removed andexamined by GPC. After 24 hours the Mn/PDI was found to 11.9/1.6. Thus,DBU complexed with less than one equivalent BA also actively causestransesterification of the poly(lactide) backbone.

Example 39 (1.0 eq. BA/DBU, 2M PLA)

In a nitrogen filled glovebox a vial was charged with PLA (0.1 g, Mn18100, PDI 1.06), DCM (0.8 mL), BA (0.0021 g, 0.0173 mmol), and astirbar. The depolymerization was then initiated by the addition of DBU(0.0026 g, 0.0173 mmol). After 24 and 48 hours aliquots were removed andexamined by GPC. After 24 hours no discernible change was observed in Mnand PDI. Thus, DBU complexed with one equivalent BA does not catalyzetransesterification of the poly(lactide) backbone, yet the adduct is anactive catalyst for ring opening polymerization, as shown in Example 33(see also Example 13).

Example 40 (1.5 eq. BA/DBU, 2M PLA)

In a nitrogen filled glovebox a vial was charged with PLA (0.1 g, Mn18100, PDI 1.06), DCM (0.8 mL), BA (0.0032 g, 0.0260 mmol), and astirbar. The depolymerization was then initiated by the addition of DBU(0.0026 g, 0.0173 mmol). After 24 and 48 hours aliquots were removed andexamined by GPC. After 24 hours no discernible change was observed in Mnand PDI. Thus, DBU complexed with 1.5 equivalents BA does not catalyzetransesterification of the poly(lactide) backbone. The adduct is aweaker catalyst for ring opening polymerization than the BA:DBU 1:1-madduct (compare Example 34 with Example 33).

Example 41C(2.0 eq. BA/DBU, 2M PLA)

In a nitrogen filled glovebox a vial was charged with PLA (0.1 g, Mn18100, PDI 1.06), DCM (0.8 mL), BA (0.0042 g, 0.0346 mmol), and astirbar. The depolymerization was then initiated by the addition of DBU(0.0026 g, 0.0173 mmol). After 24 and 48 hours aliquots were removed andexamined by GPC. After 24 hours no discernible change was observed in Mnand PDI. Thus, greater than one equivalent of BA merely lowers thecatalytic activity of the salt catalyst relative to the 1:1 adduct untilthe catalytic activity ceases at saturation point (2 equivalents BA).

Summarizing the backbone transesterification results, Examples 37C and38C show that BA:DBU salt catalyst compositions comprising less than 1mole equivalent BA per mole of DBU promote transesterification,degrading the Mn of a pre-formed poly(lactide) from about 18K to about9K, and broadening the PDI from an initial value of 1.06 to about 1.6.Examples 39, 40 and 41C show that BA:DBU salt catalyst compositionshaving greater than or equal to 1.0 mole equivalent BA per mole of DBUdo not promote transesterification, resulting in no experimentallydiscernable change in the Mn and PDI of the starting poly(lactide). Thisfinding is additionally supported by FIG. 2A and FIG. 2B, graphs showingthat Mn (and PDI) of the polymer formed in Example 13 using a BA:DBU1:1-m remains unchanged even 24 hours post complete conversion.

The above examples indicate the optimum ratio of moles of active hydroxyfunctional groups to moles of guanidine and or amidine functional groupsin the salt catalyst is about 0.95 to 1.2, more particularly, 0.95 to1.1, still more particularly 1.0 to 1.05, and most particularly about1.0.

Without being bound by theory, the trend seen in increased reactiontimes in Table 6 may be explicable in terms of catalyst deactivation.Given that the catalysis proceeds through a mechanism similar to Scheme2 (see Background section), protonation of the catalyst may lose potencytoward hydroxyl group activation. Less activation translates into aslower ring opening rate and longer polymerization times. The impact ofcatalyst deactivation on selectivity is less obvious.

Molecular modeling provided a better understanding of the role ofprotonated DBU in the ring opening reaction. Through computationalinvestigations it was found that the energetically favored acid/basecomplex was reminiscent of Scheme 3. Quantum-chemical calculations on arepresentative molecular model system were carried out at theB3LYP/aug-cc-pVTZ//B3LYP/6-31+G* density functional level with acontinuum dielectric model (IEF-cPCM) for CH₂Cl₂ (dielectric=8.9) asimplemented in GAMESS-US. The model system used was: 1) formic acid (forbenzoic acid), 2) methanol as initiator, and 3) a simplified DBU analogwith the 7-membered ring replaced by two methyl groups. The reactionstudied was the initial step of the ring-opening polymerization ofL-lactide, resulting in a reaction pathway with a rate-determining step(nucleophilic attack of the activated alcohol at the lactide carbonylcarbon) of about 19 kcal/mol. As shown in FIG. 3A, a stable salt adductis formed which is the catalytic species. This species reverses the roleof the DBU (as compared to its free base). In the adduct, the DBUelectrophilically activates the lactide carbonyl. The conjugate base ofbenzoic acid is then able to activate the hydroxyl group for thesubsequent nucleophilic attack (FIG. 3C). Through both computationallyand experimentally derived results, it was determined that saturation ofDBU with 2 molar equivalents of benzoic acid leads to an inactive saltcatalyst (FIG. 3B).

The Role of DBU.

To probe the role of DBU, other nitrogen bases were tested, as describedabove in Examples 22C, 23C, 24C, 25, and 26C. Comparing these withExamples 12 and 17, it can be seen in Table 7 that only oxoacid adductsof non-aromatic guanidine and amidine bases were found to efficientlycatalyze lactide polymerizations. It should also be noted that theactive salt catalysts were also able to form acid-base complexes havingtwo equivalents of BA, whereas all inactive nitrogen bases becamesaturated with BA upon stoichiometric equivalence.

TABLE 7 Saturation BA Salt BA:Base (BA Rxn Time Mn Example Base catalystratio Equiv.)^(a) (hours)^(b) (kDa)^(c) PDI^(c) 22C DMAP Example 3C1:1-m 1 48 N/A 23C N-Methylimidazole Example 4C 1:1-m 1 48 N/A 24CTriethylamine Example 5C 1:1-m 1 48 N/A 25 DCPG Example 10 1:1-m 2 2116   1.2 26C Phosphine Example 11C 1:1-m 1 48 N/A 27C DMAP As Ex. 3C0.5:1.0-m 1 72 4600   1.04 with 0.5 eq. BA 28C N-Methylimidazole As Ex.4C 0.5:1.0-m 1 72 N/A with 0.5 eq. BA 29C Triethylamine As Ex. 5C0.5:1.0-m 1 72 N/A with 0.5 eq. BA 30C Phosphine As Ex. 11C 0.5:1.0-m 172 N/A with 0.5 eq. BA 12 DBU Example 1 1:1-m 2 20 18.1 1.07 17 MTBDExample 2 1:1-m 2 16 17.9 1.08 ^(a)Equivelants of BA at saturation pointof base, not the amount of BA used during polymerization, determined byaddition of base to ethereal solution with excess BA. ^(b)Reaction timewhen optimized conditions were used with a BA:base mole ratio of 1:1.^(c)Data based on results obtained from a THF GPC calibrated withpolystyrene standards.

In conclusion, a stable adduct of an amidine or guanidine base and anoxoacid has been found to be an efficient and selective salt catalystfor ring opening polymerization. The salt catalysts have improvedselectivity for cyclic ester polymerization, minimizing deleterioustransesterification side reactions that cause higher polydispersity. Thesalt catalysts simultaneously activate both the cyclic monomer carbonylgroup and the nucleophilic hydroxyl group, as determined by theoreticalcomputations.

The terminology used herein is for the purpose of describing particularembodiments only and is not intended to be limiting of the invention. Asused herein, the singular forms “a”, “an” and “the” are intended toinclude the plural forms as well, unless the context clearly indicatesotherwise. It will be further understood that the terms “comprises”and/or “comprising,” when used in this specification, specify thepresence of stated features, integers, steps, operations, elements,and/or components, but do not preclude the presence or addition of oneor more other features, integers, steps, operations, elements,components, and/or groups thereof. When a range is used to express apossible value using two numerical limits X and Y (e.g., a concentrationof X ppm to Y ppm), unless otherwise stated the value can be X, Y, orany number between X and Y.

The corresponding structures, materials, acts, and equivalents of allmeans or step plus function elements in the claims below are intended toinclude any structure, material, or act for performing the function incombination with other claimed elements as specifically claimed. Thedescription of the present invention has been presented for purposes ofillustration and description, but is not intended to be exhaustive orlimited to the invention in the form disclosed. Many modifications andvariations will be apparent to those of ordinary skill in the artwithout departing from the scope and spirit of the invention. Theembodiments were chosen and described in order to best explain theprinciples of the invention and their practical application, and toenable others of ordinary skill in the art to understand the invention.

What is claimed is:
 1. A method, comprising: reacting a mixturecomprising a cyclic carbonyl monomer, a nucleophilic initiator, anoptional solvent, an optional accelerator, and a salt catalyst, therebyforming a polymer by ring-opening polymerization, wherein the saltcatalyst comprises an ionic complex of i) a nitrogen base comprising oneor more guanidine and/or amidine functional groups, and ii) an oxoacidcomprising one or more active acid groups, the active acid groupsindependently comprising a carbonyl group (C═O), sulfoxide group (S═O),and/or a phosphonyl group (P═O) bonded to one or more active hydroxygroups; wherein a ratio of moles of the active hydroxy groups to molesof the guanidine and/or amidine functional groups is 0.5 to 1.5.
 2. Themethod of claim 1, wherein a chemical formula of the salt catalystcontains no metal selected from the group consisting of beryllium,magnesium, calcium, strontium, barium, radium, aluminum, gallium,indium, thallium, germanium, tin, lead, arsenic, antimony, bismuth,tellurium, polonium, and metals of Groups 3 to 12 of the Periodic Table.3. The method of claim 1, wherein the ratio of moles of the activehydroxy groups to moles of the guanidine and/or amidine functionalgroups is 0.9 to 1.5.
 4. The method of claim 1, wherein the nitrogenbase is selected from the group consisting of2-tert-butyl-1,1,3,3-tetramethyl guanidine,2-(4-methylbenzyl)-1,1,3,3-tetramethyl guanidine,2-phenyl-1,1,3,3-tetramethylguanidine, 2-hexyl-1,1,3,3-tetraethylguanidine, 2-butyl-1,1,3,3 -tetraethylguanidine,N,N′-(dicyclohexyl)pyrrolidine-1 -carboximidamide (DCPG), 7-methyl-1,5,7-triazabicyclo(4.4.0)dec-5-ene (MTBD),1,5,7-triazabicyclo(4.4.0)dec-5-ene (TBD), N-methyl-N′,N′-diethylbenzamidine, N-benzyl-N-phenyl-N′-p-tolyl-benzamidine,1,8-diazabicyclo(5.4.0)undec-7-ene (DBU),1,5-diazabicyclo(4.3.0)non-5-ene (DBN), and combinations thereof.
 5. Themethod of claim 1, wherein the nitrogen base is selected from the groupconsisting of 7-methyl-1,5,7-triazabicyclo(4.4.0)dec-5-ene (MTBD),1,5,7-triazabicyclo(4.4.0)dec-5-ene (TBD),1,8-diazabicyclo(5.4.0)undec-7-ene (DBU),1,5-diazabicyclo(4.3.0)non-5-ene (DBN), and combinations thereof.
 6. Themethod of claim 1, wherein the nitrogen base is a polymer supportednitrogen base, comprising a repeat unit comprising a side chainguanidine and/or amidine functional group.
 7. The method of claim 1,wherein the oxoacid is selected from the group consisting of carboxylicacids, sulfuric acid, monoesters of sulfuric acid, sulfonic acids,sulfinic acids, phosphoric acid, monoesters of phosphoric acid, diestersof phosphoric acid, phosphorous acid, organophosphonic acids, monoestersof organophosphonic acids, phosphinic acid, organophosphinic acids, andcombinations thereof.
 8. The method of claim 1, wherein the oxoacid isselected from the group consisting of carboxylic acids, sulfonic acids,and combinations thereof.
 9. The method of claim 1, wherein the cycliccarbonyl monomer comprises a cyclic functional group selected from thegroup consisting of cyclic esters, cyclic carbamates, cyclic ureas,cyclic thiocarbamates, cyclic thioureas, cyclic dithiocarbonates, andcombinations thereof.
 10. The method of claim 1, wherein the cycliccarbonyl monomer is a cyclic ester.
 11. The method of claim 10, whereinthe cyclic ester is selected from the group consisting of L-lactide,D-lactide, DL-lactide, beta-butyrolactone, delta-valerolactone,epsilon-caprolactone, and combinations thereof.
 12. The method of claim1, wherein the cyclic carbonyl monomer is a cyclic carbonate.
 13. Themethod of claim 12, wherein the cyclic carbonate is selected from thegroup consisting of trimethylene carbonate, methyl5-methyl-2-oxo-1,3-dioxane-5-carboxylate, and ethyl5-methyl-2-oxo-1,3-dioxane-5-carboxylate.
 14. The method of claim 1,wherein the nucleophilic initiator is selected from the group consistingof alcohols, amines, thiols, and combinations thereof.
 15. The method ofclaim 1, wherein the nucleophilic initiator is an alcohol.
 16. Themethod of claim 1, wherein the nucleophilic initiator is a polyetheralcohol.
 17. The method of claim 1, wherein the polymer has apolydispersity index of 1.0 to 1.3.
 18. The method of claim 1, whereinthe salt catalyst is generated in situ.
 19. The method of claim 1,wherein the oxoacid is a carboxylic acid.
 20. The method of claim 1,wherein the oxoacid is a sulfonic acid.
 21. The method of claim 1,wherein the nitrogen base is a guanidine base.
 22. The method of claim1, wherein the nitrogen base is an amidine base.
 23. A method,comprising: forming a mixture comprising a cyclic carbonyl monomer, anucleophilic initiator, an optional accelerator, an optional solvent,and an oxoacid, the oxoacid comprising one or more active acid groups,the active acid groups independently comprising a carbonyl group (C═O),sulfoxide group (S═O), and/or a phosphonyl group (P═O) bonded to one ormore active hydroxy groups; and adding to the mixture a nitrogen basecomprising one or more guanidine and/or amidine functional groups,thereby forming a salt catalyst, wherein a ratio of moles of the activehydroxy groups to moles of the guanidine and/or amidine functionalgroups of the salt catalyst is 0.5to 1.5, allowing the salt catalyst tocatalyze ring opening polymerization of the cyclic carbonyl monomer,thereby forming a polymer.
 24. The method of claim 23, wherein theactive acid group comprises a carbonyl group.
 25. The method of claim23, wherein the active acid group comprises a sulfoxide group.
 26. Themethod of claim 23, wherein the active acid group comprises a phosphonylgroup.
 27. The method of claim 23, wherein the nitrogen base comprisesone or more guanidine functional groups.
 28. The method of claim 23,wherein the nitrogen base comprises one or more amidine functionalgroups.